Project Summary ?Look me straight in the eye? a parent exhorts, but for some children it is impossible because one eye is deviated. In this condition, known as strabismus, stereovision may be lost and the deviated eye may develop amblyopia. Long term consequences include reduced eye-hand coordination, diminished quality of life, employment discrimination, social prejudice, and psychological distress. The overarching goal of this project is to discover why normal binocular vision fails in some children. When children lose fusion, they avoid diplopia by suppressing portions of the visual field seen with each eye. The development of these regions, called suppression scotomas, blocks the error signal that would normally induce an adjustment in extraocular eye muscle tone to bring the eyes back together. Ophthalmologists perform surgery to align eyes, but success rates are far from satisfactory, largely because the persistence of suppression robs children of the drive to recover fusion. To find better treatments, it is imperative to understand the neural basis of suppression. This project uses a translational approach: patients with strabismus are studied to characterize their deficits, and then these deficits are probed in nonhuman primates raised with an experimental form of strabismus that closely resembles the real disease. In Aim #1, studies are focused on children with exotropia, an outwards deviation of one eye. It is usually intermittent, but ophthalmologists tend to recommend surgery, for fear that an intermittent exotropia may progress to become constant, resulting in permanent loss of binocular function. In a longitudinal observational cohort study, patients will be outfitted with a wearable eyetracker to document the frequency of episodes of exotropia during the course of daily activities. The feasibility of using this device to track disease severity in individual patients will be investigated. Data will be collected over 5 years to elucidate the natural history of this condition. In Aim #2, a new chemogenetic technique will be used to silence retinal ganglion cells that project to the superior colliculus. The role these cells play in generating eye movements is unknown, because until now, no method has existed to selectively and reversibly block them. Exotropic monkeys will be examined to determine the impact on receptive field properties and the ability to make alternating saccades. In Aim #3, suppression scotomas will be mapped dichoptically in monkeys with exotropia. Once their layout is established, recordings will be made in the primary visual cortex, to compare responses of single cells to monocular vs. binocular stimulation. For binocular testing, stimuli will be delivered to the receptive field in one eye and to a location in the other eye that is displaced by the magnitude of the ocular deviation. The hypothesis is that cells with their receptive field located in regions where perception is suppressed under binocular viewing conditions will respond more weakly during binocular stimulation than during monocular stimulation. These cortical recordings, the first conducted in alert, behaving monkeys with strabismus, may reveal the neural basis of suppression by correlating single cell firing with visual perception.